Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-β1-mediated tissue fibrosis

Avraham, Tomer; Yan, Alan; Zampell, Jamie C.; Daluvoy, Sanjay V.; Haimovitz‐Friedman, Adriana; Cordeiro, Andrew P.; Mehrara, Babak J.

doi:10.1152/ajpcell.00535.2009

Cited by 134 publications

(133 citation statements)

References 75 publications

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“…28 This effect, for example, would not diminish the action of chemotherapy in this region, since systemic treatment tends to be offered to the patients prior to radiotherapy. 29 On the assumption that the IMC incidental irradiation has a therapeutic impact, an interesting note is that precisely the group that received the higher doses to the IMC comprises mastectomy patients, regardless of whether an immediate reconstruction was performed or not.…”

Section: Discussionmentioning

confidence: 99%

Unintended irradiation of internal mammary chain – Is that enough?

Sapienza

Chen

Gomes

et al. 2016

Reports of Practical Oncology & Radiotherapy

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Section: Discussionmentioning

confidence: 99%

Unintended irradiation of internal mammary chain – Is that enough?

Sapienza

Chen

Gomes

et al. 2016

Reports of Practical Oncology & Radiotherapy

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“…Although loss of dermal lymphatic function caused by radiotherapy is described (Avraham et al, 2010), we showed that regeneration of avascular autotransplanted lymph node fragments is possible in previously irradiated regions. We exposed the rats to a single dose of radiation higher than that commonly used in human radiotherapy, so lymph node fragment regeneration in patients ought to be possible.…”

Section: Discussionmentioning

confidence: 64%

“…In future studies, we will apply the very recently described technique to visualize lymphatics in the rat (Suami et al, 2011). Assuming that superficial drainage in our rat model was totally destroyed by previous surgery and radiation, presence of local drainage seems a promising tool for future therapy, because radiation leads to a loss of dermal lymphatic vessels (Avraham et al, 2010). Regeneration of lymphatic vessels in irradiated regions seems to need longer than in nontreated areas.…”

Section: Regeneration Of Lymph Node Fragments In Ratmentioning

confidence: 99%

“…Incidence of lymphedema after lymphadenectomy in the therapy of cervical cancer or melanoma of the extremities is about 20% (for review see Norman et al, 2009). Avraham et al (2010) recently showed in a mouse model that in addition to the interruption of lymphatic vessels caused by lymphadenectomy, radiation, as in the therapy of breast cancer, causes a loss of dermal lymphatic vessels promoting the development of lymphedema after cancer therapy.…”

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confidence: 99%

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Improved Regeneration of Autologous Transplanted Lymph Node Fragments by VEGF‐C Treatment

Sommer

Büettner

Bruns

et al. 2012

The Anatomical Record

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Secondary lymphedema is a common complication after removal of lymph nodes in combination with radiation therapy in the treatment of breast cancer, cervical cancer, and melanomas. Only symptomatic therapies are available at the moment, and lymphedema is for most patients a lifelong condition involving psychological and physical disabilities. Animal models exist to study the pathophysiology of lymphedema but not to study surgical treatments. The aim of this study was to show that regeneration of autologous transplanted lymph node fragments is possible in rats that were irradiated previously locally in the groin and to examine the effects of vascular endothelial growth factor (VEGF)-C injections on the rate of regeneration of transplanted lymph nodes. In all of the animals, inguinal and popliteal lymph nodes and adjacent lymphatic vessels were unilaterally removed and the inguinal region irradiated by a single dose of 15 Gy. Afterward, lymph node fragments were transplanted subcutaneously in the irradiated region. Half of the animals were treated by local VEGF-C injections after transplantation. Four weeks after transplantation, drainage of the leg was tested by injection of blue dye, and the transplanted fragments were removed and examined immunohistologically. We could show that regeneration of autologous transplanted lymph node fragments is possible in areas treated with radiotherapy in the rat. We also documented that transplants can achieve a connection to the lymphatic collectors of the leg. The results suggest that the outcome of regeneration can be improved by injection of VEGF-C in the transplantation area. Thus, lymph node fragment regeneration may be relevant for lymphedema prevention and therapy. Anat Rec, 295:786-791, 2012. V C 2012 Wiley Periodicals, Inc.

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“…[22] Our group has previously shown that fibrosis is a critical regulator of lymphatic function and lymphatic regeneration [14,15,23,24] and fibrosis is a clinical histopathologic hallmark of lymphedema. [25] Therefore, in these experiments we sought to determine if CD4 or CD8 cell inflammation contributes to fibrosis and lymphatic dysfunction in the mouse tail model of lymphedema.…”

Section: Cd4 + Cell Depletion Inhibits Fibrosis and Improves Lymphatimentioning

confidence: 99%

Adaptive Immune Responses Regulate the Pathophysiology of Lymphedema

Zampell¹,

Mehrara²,

Weitman³

et al. 2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE 01-09-2012 REPORT TYPE Annual Summary DATES COVERED01 AUTHOR(S)Jamie Zampell, Babak Mehrara, Evan Weitman, Sonia Elhadad, Alan Yan 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: jamie.zampell@nyumc.org, mehrarab@mskcc.org, weitmane@mskcc org 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTLymphedema is a debilitating disorder affecting as many as 1 in 8 cancer survivors. Despite wide prevalence, limited understanding of disease pathogenesis has prevented development of effective treatment strategies. While inflammation, fibrosis, and lymphatic dysfunction are known clinical hallmarks, the mechanisms promoting these pathologic changes are unknown. The aim of this study therefore was to determine the cellular mechanisms regulating chronic lymphedema pathogenesis. Using a mouse models of lymphatic fluid stasis and chronic lymphedema, we show that sustained lymphatic fluid stasis leads to CD4+ T cell inflammation with a mixed T-helper cell type 1 (Th1)/T-helper cell type 2 (Th2) phenotype. Matched clinical specimens similarly demonstrate increased CD4+ T cell infiltrate and elevations in Th2-type cytokines. Furthermore, loss of CD4 prevents lymphedema development mouse models; more specifically, inhibition of Th2 differentiation through IL-4 and IL-13 blockade prevents both initiation of lymphedema development and progression of established lymphedema. Following Th2 abrogation, fibrosis is reduced, lymphatic function is improved, and lymphangiogenesis is augmented without a concomitant alteration in lymphangiogenic cytokines. The findings of this study demonstrate that lymphedema pathogenesis results from progressive lymphatic dysfunction resulting from chronic CD4+ inflammation, Th2 differentiation, and fibrosis. Blockade of Th2 res...

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Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-β1-mediated tissue fibrosis

Abstract: A, Cordeiro AP, Mehrara BJ. Radiation therapy causes loss of dermal lymphatic vessels and interferes with lymphatic function by TGF-␤1-mediated tissue fibrosis.

Cited by 134 publications

References 75 publications

Unintended irradiation of internal mammary chain – Is that enough?

Unintended irradiation of internal mammary chain – Is that enough?

Improved Regeneration of Autologous Transplanted Lymph Node Fragments by VEGF‐C Treatment

Adaptive Immune Responses Regulate the Pathophysiology of Lymphedema

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